Development of Palladium-Catalyzed C-N Bond Formation Reaction Wu Hua

First Intermolecular Carbon-Nitrogen Bond Formation In 1983 Kosugi et al. published report of intermolecular carbon-nitrogen bond formation. Only electron neutral aryl bromides gave products in good yields. Vinyl Bromides and aryl bromides containing electron donating or electron withdrawing groups gave products in low yields. Only Unhindered dialkyl amides gave good yields of amination products. M. Kosugi, M. Kameyama, T. Migita, Chem. Lett. 1983, 927

First Intramolecular Carbon-Nitrogen Bond formation First example of palladium(0) mediated carbon-nitrogen bond formation using stoichiometric quantities of palladium(0) was reported by Boger in 1984 eq. Pd(PPh 3 ) 4 SolventTemperature/ o CTime/hYield/% 1.0THF(sealed tube) THF(sealed tube) THF(sealed tube) Dioxane Dioxane Toluene THF(sealed tube)80240 D. L. Boger, J. S. Panek, Tetrahedron Lett. 1984, 3175

Catalytic examples using amino stanannes Work reported by S. Buchwald: Examples: A. S. Guram, S. L. Buchwald, J. Am. Chem. Soc. 1994, 7901.

Catalytic examples using amino stanannes Work reported by J. Hartwig: Catalytic cycle: F. Paul, J. Patt, J. F. Hartwig, J. Am. Chem. Soc. 1998, A lot of advantages !

Achieving the Same Chemistry Without the use of Tin Reagents Work reported by J. Hartwig: Catalytic cycle: J. Louie, J. F. Hartwig, Tetrahedron Lett. 1995, 3609.

Achieving the Same Chemistry Without the use of Tin Reagents Work reported by S. Buchwald: Tested a variety of aryl iodides with primary and secondary amines: Good yields for all, 59-79%. J. P. Wolfe, S. L. Buchwald, J. Org. Chem. 1996, 1133.

Catalyst Development Buchwald found dramatic improvements in yield and substrate generality by using BINAP as the ligand Catalyst loadings are also significantly reduced Compared with 35% when using P(o-tolyl) 3 and R = n-hexyl RMol% PdReaction time/hYield/% n-hexyl Bn Bn Cyclohexyl J. P. Wolfe, S. Wagaw, S. L. Buchwald, J. Am. Chem. Soc. 1996, 7215.

BINAP Reaction Mechanism

Catalyst development Hartwig developed a dppf based system that shows enhanced catalytic qualities Good for primary amines and works on electron deficient aryl halides M. S. Driver, J. F. Hartwig, J. Am. Chem. Soc. 1996, 1133.

Coupling of Secondary Acyclic Amines LigandTime/hIsolated yield/% P(o-tolyl) BINAP48- DPPF48- (rac)-BPPFA48- FcPPh (rac)-PPFA2489 (rac)-PPF-OMe593 J. Marcoux, S. Wagaw, S. L. Buchwald, J. Org. Chem. 1997, 1568.

Coupling of Aryl Triflates Buchwald: Hartwig: Both systems use electron rich and electron poor aryl triflates with primary and secondary amines (cyclic and acyclic) J. P. Wolfe, S. L. Buchwald, J. Org. Chem. 1997, J. Louie, M. S. Driver, B. C. Hamann, J. F. Hartwig J. Org. Chem. 1997, 1268.

Intermolecular Markovnikov Hydroamination of vinylarenes with alkylamines Via: Products formed in % yield M. Utsunomiya, J. F. Hartwig, J. Am. Chem. Soc. 2003,

Synthesis of Enamines and Imines Examples: M. Fernández, F. Aznar, C. Valdés, J. Barluenga, Chem. Eur. J. 2004, 494.

Scope and Limitations of the Pd/BINAP-Catalyzed Amination of Aryl Bromides John P. Wolfe, Stephen L. Buchwald. J. Org. Chem. 2000, 65, Catalytic Amination of Aryl Bromides Using NaO-t-Bu as the Base. Note: When the weak base Cs 2 CO 3 is employed, a much wider variety of functional groups are tolerated.

Tanoury, G. J. Senanayake. Tetrahedron Lett. 1998, 39, 6845 Application In The Synthesis

Hong. Y. Tetrahedron Lett. 1998, 39, 3121 Selective Cross-Coupling Using BINAP

Stephen L. Buchwald. J. Am. Chem. Soc. 2003, 125,

Jacqueline E. Milne, Stephen L. Buchwald. J. Am. Chem. Soc. 2004, 126,

Eric R. Strieter, Stephen L. Buchwald. Angew. Chem. Int. Ed. 2006, 45, 925 –928 Catalyst Activation Mechanism

Stephen L. Buchwald. J. Am. Chem. Soc. 2007, 129,

A New Class of Air- and Moisture- stable Pd Precatalysts They are particularly useful in cases where a highly active Pd complex is required to promote a difficult cross-coupling reaction or where functional group instability requires the use of low temperatures. Mark R. Biscoe, Brett P. Fors, Stephen L. Buchwald. J. Am. Chem. Soc. 2008, 130, 6686–6687

Chemoselective Cross-coupling Reactions Debabrata Maiti and Stephen L. Buchwald. J. Am. Chem. Soc. 2009, 131, 17423–17429

Stephen L. Buchwald. J. Am. Chem. Soc. 2009, 131, 16720–16734

Kelvin Billingsley, Stephen L. Buchwald. J. Am. Chem. Soc. 2007, 129, Application In Suzuki-Miyaura Reaction Reduce the loading of catalyst !

Brett P. Fors, Stephen L. Buchwald. J. Am. Chem. Soc. 2009, 131, 12898–12899

First, the dative ancillary ligands can be displaced by ammonia to form a catalytically unreactive complex. Second, reductive elimination from an Ar-Pd-NH 2 complex has never been observed, perhaps because complexes of the parent amido group often adopt stable bridging structures. Third, if reductive elimination did form the arylamine, this product would likely be more reactive than ammonia and would further react to form the diarylamine. Cross-coupling Reaction With Ammonia Difficulties Suffered:

Qilong Shen and John F. Hartwig. J. Am. Chem. Soc. 2006, 128,

(i) many kinds of transition metals are deactivated by ammonia to give stable amine complexes and (ii) when a reaction forms a primary amine, this product is more reactive than ammonia and causes problematic overreactions. It is noteworthy that the use of aqueous ammonia is essential and that ammonia gas did not react at all !. Takashi Nagano and Shu Kobayashi. J. Am. Chem. Soc. 2009, 131, 4200–4201

Palladium-Catalyzed Asymmetric Dearomatization of Naphthalene Derivatives Stephen L. Buchwald. J. Am. Chem. Soc. 2009, 131, 6676–6677

Conclusion First-generation catalyst: Pd/P(o-tolyl) 3 Second-generation catalyst: Pd/aromatic phosphines Third-generation catalyst: Pd/Hindered alkylphosphines BINAPDPPF

1.One kind of the Buchwald-Hartwig cross-coupling reaction substrates must be aryl halides and aliphatic halides have not been reported. 2. It will be paid more attention to its use in asymmetric synthesis.